This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. DNA can be damaged by both environmental and intra-cellular agents. Failure to repair DNA can cause genetic instability and mutations that lead to various human diseases, including cancer. Therefore, understanding the mechanisms by which DNA repair proteins function have important biological and clinical relevance. Structural studies of DNA repair proteins using X-ray crystallography are critical in deciphering these important mechanisms. Brief descriptions of the biological questions to be studied are as follows. First, to understand how the gene products that cause inherited forms of cancers, interact with one another. Such structural studies will contribute greatly to how DNA damage signaling and recruitment of DNA repair complexes are coordinated and how their mutations may lead to cancer. Second, there are tumor suppressors whose mutations are found in cancer, but whose functions are not yet known. In order to gain a better insight into these uncharacterized tumor suppressors in normal and diseased cellular processes, we wish to elucidate their three-dimensional structures using x-ray crystallography. Third, when DNA is exposed to genotoxic agents including ultraviolet light from the sun and toxic chemicals, one of the earliest cellular event is recognition of the damaged DNA. Structural insights into how DNA-sensor proteins recognize and bind stably to various damaged DNA-structures will be invaluable in understanding the etiology of human diseases related to genomic instability, including cancer and mental retardation.